Dual on‐demand delivery of therapeutic cargos and energy by transporters can latently mitigate side effects and provide the unique aspects required for precision medicine. To achieve this goal, metal‐organic frameworks (MOFs), hybrid materials constructed from metal ions and polydentate organic linkers, have attracted attention for controlled drug release and energy delivery in tumors. With appropriate characteristics such as tunable pore size, high surface area, and tailorable composition, therapeutic agents (drug molecules or responsive agents) can be effectively encapsulated in MOFs. Based on their intrinsic properties, many physically or chemically responsive agents are able to achieve precise on‐demand drug release and energy generation (thermal or dynamic therapy) using MOFs (as energy absorbers). Herein, the results obtained with various stimuli‐responsive MOFs (including materials from the Institute Lavoisier [MIL], zeolitic imidazolate frameworks [ZIFs], MOFs from the University of Oslo [UiO], and other MOFs) used for tumor suppression are summarized. Furthermore, with the appropriate stimulus, catalytic therapy (caused by the Fenton reaction induced by MOFs) can be provided via the utilization of existing high levels of H2O2 in cancer cells, which potentially elicits immune responses. In addition, the issues impeding clinical translation are also discussed, including the need to overcome tumor heterogeneity and to recognize the innate immune system and possible effects. As the references reveal, additional comprehensive strategies and studies are needed to enable broad applications and potent translational developments.

T lymphocyte recruitment and infiltration promises to suppress the most devastating metastatic tumors for immunotherapy. However, the immune privilege and low vaccine immunogenicity usually reduces the presence of lymphocytes in tumors, especially for invading metastatic clusters. Here, an adhesive catalytic nanoreservoir (CN) containing manganese dioxide (MnO2) and catechol‐functionalized magnetic metal organic framework for the antigens capture and delivery is reported. The intravenously injected CN accumulates at tumor via the marginated target and in situ forming gel for antigen capture. At tumor site, CN releases Mn2+ for redox reactions by depleting glutathione (GSH) and Fenton‐like activity, i.e., chemodynamic therapy (CDT). Accompanying with hyperthermia, CDT promote the tumor to release the tumor‐associated antigens including neoantigens and damage‐associated molecular patterns. Then, the gels with catechol groups act as antigen reservoirs and deliver the autologous tumor‐associated antigens to dendritic cells, achieving sustained immune stimulation. The in situ‐forming catalytic nanoreservoir at lung metastasis as a magnetothermal‐induced antigen reservoir effectively inhibited the tumor in 60 days and increased the survival rate.

Nano-catalytic agents actuating Fenton-like reaction in cancer cells cause intratumoral generation of reactive oxygen species (ROS), allowing the potential for immune therapy of tumor metastasis via the recognition of tumor-associated antigens. However, the self-defense mechanism of cancer cells, known as autophagy, and unsustained ROS generation often restricts efficiency, lowering the immune attack, especially in invading metastatic clusters. Here, a functional core-shell metal-organic framework nanocube (dual MOF) doubling as a catalytic agent and T cell infiltration inducer that programs ROS and inhibits autophagy is reported. The dual MOF integrated a Prussian blue (PB)-coated iron (Fe2+)-containing metal-organic framework (MOF, MIL88) as a programmed peroxide mimic in the cancer cells, facilitating the sustained ROS generation. With the assistance of Chloroquine (CQ), the inhibition of autophagy through lysosomal deacidification breaks off the self-defense mechanism and further improves the cytotoxicity. The purpose of this material design was to inhibit autophagy and ROS efficacy of the tumor, and eventually improve T cell recruitment for immune therapy of lung metastasis. The margination and internalization-mediated cancer cell uptake improve the accumulation of dual MOF of metastatic tumors in vivo. The effective catalytic dual MOF integrated dysfunctional autophagy at the metastasis elicits the ~3-fold recruitment of T lymphocytes. Such synergy of T cell recruitment and ROS generation transported by dual MOF during the metastases successfully suppresses more than 90% of tumor foci in the lung.

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